Process for the preparation of 4-alkoxy-3-hydroxypicolinic acids

ABSTRACT

4,6-Dibromo-3-hydroxypicolinonitrile may be prepared from furfural in a series of chemical steps selected from cyano-amination, amine salt formation and bromination-rearrangement. 4-Alkoxy-3-hydroxypicolinic acids may be conveniently prepared from 4,6-dibromo-3-hydroxypicolinonitrile in a series of chemical steps selected from bromo substitution, nitrile hydrolysis and halogen reduction.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/021,876 filed Jul. 8, 2014, 62/021,877 filedJul. 8, 2014, and 62/021,881 filed Jul. 8, 2014 each of which isexpressly incorporated by reference herein in its entirety as if eachwere incorporated by reference herein individually.

FIELD

The present disclosure concerns a process for the preparation of4-alkoxy-3-hydroxypicolinic acids. More particularly, the presentdisclosure concerns a process for the preparation of4-alkoxy-3-hydroxypicolinic acids from furfural.

BACKGROUND

U.S. Pat. No. 6,521,622 B1 and U.S. Application Ser. Nos. 61/747,723 and14/142,183, the disclosures of which are hereby incorporated byreference in their entireties, describe inter alia certain heterocyclicaromatic amide compounds of general Formula

and their use as fungicides.

These disclosures also describe the preparation of4-alkoxy-3-hydroxypicolinic acids as key intermediates in thepreparation of these heterocyclic aromatic amide compounds. It would beuseful to have an efficient and scalable process route to4-alkoxy-3-hydroxypicolinic acids from inexpensive raw materials.

SUMMARY

A first set of aspects of the invention include a biphasic process forthe preparation of the compound of Formula A:

comprising the steps of: a) creating a first mixture by combiningtogether a 2-phase water-organic solvent system, an ammonia source, acyanide source and a furan-2-aldehyde of Formula B:

b) separating a second mixture from the first mixture which includes thecompound of Formula C as a solution in the organic solvent;

c) adding an aqueous solution of a mineral acid to the second mixture toform a third mixture; d) separating a fourth mixture from the thirdmixture which is an aqueous mixture that includes the compound offormula D;

wherein X is Br, HSO₄, NO₃ or H₂PO₄; e) adding a brominating agent tothe fourth mixture to form a fifth mixture; and f) isolating thecompound of Formula A from the fifth mixture. In some embodiments theorganic solvent is at least one organic solvent selected from the groupof organic solvents consisting of: diethyl ether, methyl t-butyl ether,methylene chloride, ethyl acetate, 2-methyltetrahydrofuran, toluene andxylene. In some embodiments the mineral acid is hydrobromic acid. Insome embodiments X is Br. In some embodiments brominating agent isbromine.

A second set of aspects of the invention include a process that includesthe process of the first aspect and further comprises the steps of: a)creating a sixth mixture which includes the alkali metal alkoxide ofFormula EMOR¹  Ewherein M is Na or K, and R¹ is a C₁-C₃ alkyl; andthe compound of Formula A;

b) heating the mixture; and

c) isolating a compound of Formula F from the sixth mixture;

wherein R¹ is a C₁-C₃ alkyl. Some embodiments further comprise the stepsof: a) creating a seventh mixture which includes the compound of FormulaF, water, and at least one of a mineral acid and a strong base; b)heating the mixture; and c) isolating the compound of Formula G

wherein R¹ is a C₁-C₃ alkyl; from the seventh mixture. In someembodiments the seventh mixture includes the compound of Formula F,water, and a mineral acid. In some embodiments the mineral acid issulfuric acid. In some embodiments the seventh mixture includes thecompound of Formula F, water, and a strong base. In some embodiments thestrong base is at least one strong base selected from the groupconsisting of: sodium hydroxide and potassium hydroxide.

A third set of aspects includes the steps of the second aspect andfurther comprise the following steps: a) creating an eighth mixturewhich includes the compound of Formula G and a reducing agent; and b)isolating the compound of Formula H from the eighth mixture;

wherein R¹ is a C₁-C₃ alkyl. In some embodiments the reducing agent iscomprised of hydrogen and a transition metal catalyst. In someembodiments the hydrogen is hydrogen gas and the transition metalcatalyst is comprised of palladium on carbon. In some embodiments thereducing agent is comprised of zinc metal.

A fourth set of aspects includes the steps of the second aspect furthercomprising the steps of: further comprising the following steps: a)creating a ninth mixture which includes the compound of Formula F and areducing agent; and b) isolating the compound of Formula I from theninth mixture;

wherein R¹ is a C₁-C₃ alkyl. In some embodiments the reducing agent iscomprised of hydrogen and a transition metal catalyst. In someembodiments the reducing agent is comprised of zinc metal. In someembodiments the process further comprises the steps of: a) creating atenth mixture which includes the compound of Formula I, water, and oneof a mineral acid and a strong base; and b) isolating a compound ofFormula H from the tenth mixture;

wherein R¹ is a C₁-C₃ alkyl. In some embodiments the process furthercomprising the step of; heating the tenth mixture. In some embodimentsthe tenth mixture includes the compound of Formula I, water, and amineral acid. In some embodiments the mineral acid is sulfuric acid. Insome embodiments the tenth mixture includes the compound of Formula I,water, and a strong base. In some embodiment the strong base is at leastone strong base selected from the group consisting of: sodium hydroxideand potassium hydroxide.

A fifth aspect of the invention includes a process for preparing thecompound of Formula H

comprises the steps of: a) creating a mixture which includes thecompound of Formula F,

wherein R¹ is a C₁-C₃ alkyl; a strong base, zinc metal, and water; b)heating the mixture; and c) isolating the compound of Formula H from themixture. In some embodiments the strong base is potassium hydroxide.

A sixth aspect of the invention includes a process for preparing thecompound of Formula F

wherein R¹ is a C₁-C₃ alkyl; comprising the steps of: a) creating amixture which includes at least one alkali metal alkoxide of Formula EMOR¹  Ewherein M is Na or K, and R¹ is a C₁-C₃ alkyl; andthe compound of Formula A;

b) heating the mixture; and c) isolating a compound of Formula F fromthe mixture. In some embodiments M is Na and R¹ is a C₁-C₃ alkyl. Someembodiments further comprise a solvent mixture comprised of a proticsolvent and a polar aprotic solvent. In some embodiments the proticsolvent is selected is at least one solvent selected from the groupconsisting of: methanol and ethanol. In some embodiments the aproticsolvent is at least one solvent selected from the group consisting of:DMSO, DMF, sulfolane and NMP. In some embodiments the volume percentratio of the protic solvent to the polar aprotic solvent in the solventmixture is from about 100:0 to about 0:100.

Some aspects of the present disclosure concerns processes for thepreparation of 4-alkoxy-3-hydroxypicolinic acids of Formula H

wherein R¹ is a C₁-C₃ alkyl; from the compound of Formula A

The compound of Formula A may be prepared in a biphasic process whichcomprises the following steps: a) creating a first mixture by combiningtogether a 2-phase water-organic solvent system, an ammonia source, acyanide source and a furan-2-aldehyde of Formula B

b) separating a second mixture from the first mixture containing thecompound of Formula C as a solution in the organic solvent;

c) adding an aqueous solution of a mineral acid to the second mixture toform a third mixture; d) separating a fourth mixture from the thirdmixture that is an aqueous mixture containing the compound of formula D;

wherein X is Br, HSO₄, NO₃ or H₂PO₄; e) adding a brominating agent tothe fourth mixture to form a fifth mixture; and f) isolating thecompound of Formula A from the fifth mixture.

The compound of Formula H may be prepared in a process that comprisesthe following steps: a) creating a first mixture containing the alkalimetal alkoxide of Formula EMOR¹  Ewherein M is Na or K, and R¹ is a C₁-C₃ alkyl; and the compound ofFormula A; b) heating the mixture; and c) isolating a compound ofFormula F from the first mixture

wherein R¹ is a C₁-C₃ alkyl; c) creating a second mixture containing thecompound of Formula F, water, and one of a mineral acid and a strongbase; d) heating the second mixture; e) isolating a compound of FormulaG from the second mixture

wherein R¹ is a C₁-C₃ alkyl; f) creating a third mixture containing thecompound of Formula G and a reducing agent; and g) isolating thecompound of Formula H from the third mixture;

wherein R¹ is a C₁-C₃ alkyl.

The compound of Formula H may also be prepared in a process thatcomprises the following steps: a) creating a first mixture containingthe compound of Formula F and a reducing agent; b) isolating thecompound of Formula I from the first mixture

wherein R¹ is a C₁-C₃ alkyl; c) creating a second mixture containing thecompound of Formula I, water and one of a mineral acid and a strongbase; d) heating the second mixture; and e) isolating the compound ofFormula H from the second mixture

wherein R¹ is a C₁-C₃ alkyl.

The compound of Formula H may also be prepared in a one-pot process thatcomprises the following steps: a) creating a first mixture containingthe compound of Formula F,

wherein R¹ is a C₁-C₃ alkyl; a strong base, zinc metal and water; b)heating the mixture; and c) isolating the compound of Formula H from themixture, wherein R¹ is as previously defined.

The compound of Formula F

wherein R¹ is a C₁-C₃ alkyl; may be prepared in a process that comprisesthe following steps: a) creating a mixture containing the alkali metalalkoxide of Formula EMOR¹  Ewherein M is Na or K, and R¹ is a C₁-C₃ alkyl; and the compound ofFormula A; and b) isolating the compound of Formula F from the mixture

wherein R¹ is a C₁-C₃ alkyl.

DETAILED DESCRIPTION

The terms “isolate,” “isolating,” or “isolation” as used herein mean topartially or completely remove the desired product from the othercomponents of a finished chemical process mixture using standard methodssuch as, but not limited to, filtration, extraction, distillation,crystallization, centrifugation, trituration, liquid-liquid phaseseparation or other methods known to those of ordinary skill in the art.The isolated product may have a purity that ranges from ≦50% to ≧50%,and may be purified to a higher purity level using standard purificationmethods. The isolated product may also be used in a subsequent processstep with or without purification.

In the processes described herein 4-alkoxy-3-hydroxypicolinic acids areprepared from furfural in a series of chemical steps involvingcyano-amination, ammonium salt formation, bromination/rearrangement,bromo substitution by an alkoxide group, nitrile hydrolysis, and halogenreduction. Some of the individual steps may be performed in differentsequences of order.

Cyano(furan-2-yl)methanaminium chloride salts of Formula 1a have beenprepared and used as intermediates in the preparation of3-hydroxypicolinonitriles and 3-hydroxypicolinoamides of Formula 1b asdescribed in Acta Chem. Scand. 19 (1965) pg. 1147-1152,

wherein R² is H or methyl, R³ is H or 2-propyl, and R⁴ is CN or C(O)NH₂.

A. Preparation of Compound of Formula A

In the process described herein, chemical steps a, b and c are performedas depicted in Scheme I to prepare dibromohydroxypicolinonitrile A.

The cyano(furan-2-yl)methanaminium halide salt of Formula D is preparedby first reacting furfural (Formula B) with at least one equivalent eachof an ammonia source and

a cyanide source (Step a) in a reaction known in the art as the Streckersynthesis of -aminonitriles which is described in Organic Syntheses,Coll. Vol. I, page 21 and Coll. Vol. III, pages 84 and 88 to provide theamino(furan-2-yl)acetonitrile of Formula C. Suitable ammonia sourcesinclude: ammonium salts such as, but not limited to, ammonium acetate,ammonium bromide, ammonium chloride, ammonium formate, ammonium sulfateand ammonium cyanide; ammonia dissolved in an organic solvent such as,for example, ammonia in methanol, ammonia in ethanol and ammonia indioxane; ammonia in water (i.e., ammonium hydroxide); and liquid,anhydrous ammonia or gaseous ammonia. Suitable cyanide sources include:cyanide salts such as, but not limited to, sodium cyanide, potassiumcyanide and ammonium cyanide; and hydrogen cyanide which may be added ina continuous-addition manner with ammonia to the furfural. The reactionmay be carried out in a protic solvent or reaction medium such as wateror an alcohol, or mixtures of water and an alcohol such as, for example,water-methanol or water-ethanol, or mixtures of water with a polar,water soluble organic solvent such as, for example, tetrahydrofuran,DMSO, dioxane and acetonitrile, or mixtures thereof. Alternatively, thisreaction (Step a) may be carried out in a 2-phase solvent systemconsisting of water and at least one water immiscible solvent selectedfrom, but not limited to, diethyl ether, methyl t-butyl ether (MTBE),ethyl acetate, methylene chloride, 2-methyltetrahydrofuran (2-MeTHF),toluene and xylene. Such a reaction has been described in WO Application2000049008, page 55. The present reaction is typically conducted withagitation sufficient to maintain an essentially uniform mixture of thereactants. A typical reaction generally may require from about 1 toabout 50 hours to proceed to completion. Such a reaction may beconducted at temperatures between about 0° C. and about 50° C., orpreferably at temperatures between about 0° C. and about 30° C. Afterthe reaction is complete, the amino(furan-2-yl)acetonitrile of Formula Cmay be recovered by employing standard isolation and purificationtechniques or it may be directly converted to the compound of Formula Dwithout discreet isolation of the product of Formula C. It may bepreferable to directly convert the product of Formula C into the salt ofFormula D rather than storing it for extended periods.

In Step b of the sequence of reactions to prepare the compound ofFormula D, at least one equivalent of a mineral acid is added to theintermediate amino(furan-2-yl)acetonitrile product of Formula Cdissolved in a water immiscible solvent such as, for example, diethylether, MTBE, ethyl acetate, 2-MeTHF, toluene, xylene, or mixturesthereof, to provide the desired cyano(furan-2-yl)methanaminium salt ofFormula D. Suitable mineral acids may include, but are not limited to,hydrobromic acid (HBr), nitric acid (HNO₃), sulfuric acid (H₂SO₄), andphosphoric acid (H₃PO₄). The present reaction may be conducted attemperatures of from about 0° C. to about 25° C. After the reaction iscomplete the desired product is recovered by employing standardisolation and purification techniques.

In the bromination/rearrangement reaction (Scheme I, Step c), thecyano(furan-2-yl)methanaminium salt of Formula D is reacted with abrominating agent to provide the brominated/rearrangement product ofFormula A. The starting material of Formula D as the bromide salt, forexample, may be treated with a suitable brominating agent such asbromine, 1,3-dibromo-5,5-dimethylhydantoin or N-bromosuccinimide. Fromabout 3 to about 6 molar equivalents of the brominating agent may beused. The reaction is preferably conducted using about 3-5 molarequivalents of bromine and the bromide salt of the compound of Formula D(X═Br). It is often convenient to use an excess of the brominating agentsuch as a 5%, 10% or 15% molar excess, to insure the reaction proceedsto completion. The reaction is preferably carried out in a proticsolvent or reaction medium such as water, or mixtures of water and awater soluble, organic solvent such as, for example, methanol,

ethanol, tetrahydrofuran, dioxane or acetonitrile. The temperature atwhich the reaction is conducted is between about 0° C. and about 60° C.and preferably between about 0° C. and about 40° C. Upon completion ofthe addition of the brominating agent, the reaction mixture may beallowed to stir at room temperature for 10-48 hours. Optionally, thereaction time may be shortened by adding a base such as, for example,2-4 molar equivalents of sodium acetate, to the reaction. Optionally,after addition of the brominating agent is complete, the reaction may beheated at 30-60° C. to complete conversion to the product of Formula A.After the reaction is complete the desired product is recovered byemploying standard isolation and purification techniques.

An embodiment of the present disclosure involves the preparation of thecompound of Formula A in a “one-pot” process from furfural. In such aprocess all reaction steps may be conducted in a single vessel wherebythe reactants and reagents are sequentially added to the vessel andthen, after completion of chemical steps a and c, an isolation operationis conducted to isolate the product of Formula A. Using the chemicalreactants and reagents described herein, a cyanide source, an ammoniumsource and furfural are combined together in a reaction vessel with asolvent and sufficiently agitated at a suitable temperature and

for a suitable time to produce the amino(furan-2-yl)acetonitrile productof Formula C. The resulting reaction mixture containing the product ofFormula C is then treated with a brominating agent, such as bromine,optionally using a base, and utilizing suitable reaction conditions(time, temperature and/or solvent) as described herein to provide theproduct of Formula A. The product of Formula A is then recovered fromthe reaction mixture and purified as needed by employing standardisolation and purification techniques.

Another embodiment of the present disclosure involves preparation of thecompound of Formula A by a process referred to herein as the biphasicprocess. “Biphasic process” as used herein refers to a process thatemploys a 2-phase solvent system. As such, a 2-phase solvent system forthe Strecker synthesis of the -aminoacetonitrile of Formula C was usedemploying the conditions, chemical reactants and reagents describedherein. Use of the 2-phase solvent system, which includes water and awater-immiscible organic solvent, allows for easy separation of watersoluble salts present after the Strecker reaction (i.e., cyanide andacetate salts). The -aminoacetonitrile product remaining in the organicsolvent is then extracted into an aqueous hydrobromic acid (HBr)solution by formation of the corresponding water soluble HBr salt(compound of Formula D; X═Br). Treatment of the resulting aqueoussolution of the HBr salt of the -aminoacetonitrile with bromine affordsthe product of Formula A. The product of Formula A is then recoveredfrom the final reaction mixture and purified as needed by employingstandard isolation and purification techniques. The biphasic process maybe conducted at temperatures between about 0° C. and about 50° C. orpreferably between about 15° C. and about 35° C.

Another embodiment of the present disclosure involves the preparation ofthe compound of Formula A in a process comprising two chemical steps(i.e., the two-step process) from the cyano(furan-2-yl)methanaminiumsalt of Formula D, wherein X is as described herein. In such a process,the compound of Formula D is first reacted with from about 1 to about 2molar equivalents of a brominating agent to provide the3-hydroxy-picolinonitrile product of Formula J. The product of Formula Jis then recovered by employing standard isolation and purificationtechniques and is then treated with from about 2 to about 3 molarequivalents of the brominating agent to furnish the product of FormulaA.

The two-step process may be conducted using bromine and the bromide saltof the compound of Formula D (X═Br). It is often convenient to use anexcess of the brominating agent such as a 5%, 10% or 15% molar excess,to insure the individual reactions proceed to completion. There may besmall amounts of the intermediate mono-brominated products (i.e.,4-bromo- and/or 6-bromo-3-hydroxypicolinonitrile) present in theisolated product of Formula A. The reactions for the 2-step process maybe carried out in a protic solvent or reaction medium such as water, ormixtures of water and a water soluble, organic solvent such as, forexample, methanol, ethanol, tetrahydrofuran, dioxane or acetonitrile.The temperature at which the reactions may be conducted are betweenabout 0° C. and about 75° C. Upon completion of the addition of thebrominating agent, the reaction mixture may be allowed to stir at roomtemperature for 0-48 hours. Optionally, the conversion of the compoundof Formula J to the compound of Formula A with a brominating agent maybe conducted with an added base such as, for example, 2-4 molarequivalents of sodium acetate. After the reactions are complete thedesired product is recovered by employing standard isolation andpurification techniques.B. Preparation of Compound of Formula H

The chemical steps d, e and f may be performed as depicted in Scheme IIin two different sequences to prepare the 4-alkoxy-3-hydroxypicolinicacid of Formula H. In the substitution reaction to replace the 4-bromogroup of the compound of Formula A with an alkoxy group (Step d), use ofan alkali metal alkoxide of formula MOR¹ (M is an alkali metal; R¹ is aC₁-C₃ alkyl) produces the 4-alkoxy-6-bromo-3-hydroxypicolinonitrile ofFormula F. At least 2 equivalents, and preferably 2-5 equivalents, ofthe alkali metal alkoxide are used in this reaction. Typical alkalimetal alkoxides useful in this reaction include sodium

or potassium, methoxide, ethoxide, 1-propoxide or 2-propoxide. Thereaction may be carried out in a protic solvent or reaction medium suchas methanol (for methoxide), ethanol (for

ethoxide), 1-propanol (for 1-propoxide) or 2-propanol (for 2-propoxide),or mixtures of methanol, ethanol, 1-propanol or 2-propanol with a polar,aprotic co-solvent such as DMSO, DMF, sulfolane or NMP. The reaction mayalso be conducted with an alkali metal alkoxide in one or more of thepolar, aprotic solvents in the absence of an alcohol co-solvent. Thetemperature at which the reaction is conducted is between about 20° C.and about 150° C., preferably between about 40° C. and about 100° C. Thesubstitution reaction generally requires from about 1 to about 48 hoursto proceed to completion and may be conducted under pressure in a sealedvessel to prevent the loss of volatile solvents. After the reaction iscomplete, the desired product is recovered by employing standardisolation and purification techniques.

In some embodiments the preparation of the compound of Formula F fromthe compound of Formula A may be conducted by employing solvent mixturesincluding at least one of a protic solvent and a polar aprotic solventwhereby the volume percent (vol %) ratio of the protic solvent to thepolar aprotic solvent in the total solvent mixture ranges from about100:0 to about 0:100. In some embodiments the volume percent (vol %)ratio of the protic solvent to the polar aprotic solvent in the totalsolvent mixture is 80-100 vol % protic solvent to 0-20 vol % polaraprotic solvent, 60-80 vol % protic solvent to 20-40 vol % polar aproticsolvent, 40-60 vol % protic solvent to 40-60 vol % polar aproticsolvent, 20-40 vol % protic solvent to 60-80 vol % polar aproticsolvent, or 0-20 vol % protic solvent to 80-100 vol % polar aproticsolvent. Preferable volume percent (vol %) ratios of the protic solventto the polar aprotic solvent are from about 0.01-10 vol % protic solventto about 90-99.99 vol % polar aprotic solvent. In some embodiments thesolvent mixtures used to prepare the compound of Formula F (R¹═CH₃) fromthe compound of Formula A are methanol and DMSO, methanol and DMF,methanol and sulfolane, or methanol and NMP.

In the hydrolysis reaction of the nitrile group of the4-alkoxy-3-hydroxypicolinonitriles of Formulas F and I to produce the4-alkoxy-3-hydroxypicolinic acids of Formulas G and H, respectively(Steps e in Scheme II), the starting picolinonitriles are typicallysuspended in a strong, aqueous mineral acid reaction medium and heatedfor a period of time at elevated temperature with good mixing. Strongmineral acids useful in the hydrolysis reaction include sulfuric acid,phosphoric acid, hydrochloric acid and hydrobromic acid. Preferred,strong mineral acid reaction mediums include aqueous sulfuric acidmixtures such as about 25%, about 30%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75% orabout 80% sulfuric acid in water on a weight basis. Most preferably,from about 25% to about 70% sulfuric acid in water may be used. Thetemperature at which the hydrolysis reaction may be conducted is usuallybetween about 75° C. and about 150° C. and preferably between about 80°C. and about 120° C. The hydrolysis reaction generally requires fromabout 8 to about 48 hours, preferably from about 8 to about 36 hours, toreach completion. After the reaction is complete, the desired product

is recovered by cooling and slowly pouring the reaction mixture intocold water and employing standard isolation and purification techniques.

In some embodiments, the hydrolysis reaction of the nitrile group of the4-alkoxy-3-hydroxypicolinonitriles of Formulas F and I to produce the4-alkoxy-3-hydroxypicolinic acids of Formulas G and H, respectively(Steps e in Scheme II), the starting picolinonitriles are suspended inan aqueous reaction medium containing a strong base, such as anhydroxide of an alkali or alkaline earth metal, and heated for a periodof time at elevated temperature with good mixing. Strong bases for usein the hydrolysis of the picolinonitriles include sodium hydroxide andpotassium hydroxide. The concentration of the strong base used in thehydrolysis of the picolinonitriles may range from about 10 to about 40weight percent (wt %), from about 15 to about 40 wt %, from about 20 toabout 40 wt %, from about 30 to about 40 wt %, or from about 15 to about25 wt %. The molar equivalent ratio of strong base to the nitrilestarting material for the hydrolysis reaction may range from about 3:1to about 10:1, preferably from about 4:1 to about 7:1. The temperatureat which the strong base hydrolysis reaction may be conducted is usuallybetween about 75° C. and about 150° C. and preferably between about 80°C. and about 120° C. The strong base hydrolysis reaction generallyrequires from about 8 to about 48 hours, preferably from about 8 toabout 36 hours, to reach completion. After the hydrolysis reaction iscomplete, the desired product may be isolated by acidifying the reactionmixture and employing standard isolation and purification techniques.

Removal of the bromo group from the 6-position of the compound ofFormula F or the compound of Formula G, to produce the reduced productsof Formulas I and H, respectively (Steps f in Scheme II), may beachieved by: (1) catalytic reduction using a hydrogen source and atransition metal catalyst, or (2) reduction with a metal such as zincand a base such as potassium hydroxide or sodium hydroxide.

In the catalytic reduction with hydrogen, suitable hydrogen sourcesinclude hydrogen gas or hydrogen transfer reagents such as ammonium,potassium or sodium formate. Suitable transition metal catalystsinclude, but are not limited to, palladium on carbon (Pd/C) and Raneynickel (Ra/Ni). These catalysts may be used at levels from about 0.01%to about 10% on a weight basis of the metal to the bromopyridinesubstrate. Exemplary solvents for use in this reaction include methanol,ethanol, isopropanol, ethyl acetate, and acetic acid. A soluble basesuch as, for example, triethylamine is normally used in the catalyticreduction with hydrogen.

From about 2 to about 4 molar equivalents of the soluble base arenormally used. When hydrogen gas is used as the hydrogen source, thereduction reaction may be conducted under an atmospheric pressure ofhydrogen gas, or at elevated pressures of hydrogen gas such as 10, 20,30, 40, 50, 60, 70, 80, 90, 100 pounds or more, per square inch (psi)above atmospheric pressure, or incremental hydrogen gas pressuresbetween these values. It is preferable to use the catalytic reductionchemistry for the reduction of the 6-bromopicolinic acid of Formula G toproduce the picolinic acid of Formula H. After the catalytic reductionreaction is complete, the desired product is recovered by employingstandard isolation and purification techniques.

In the reduction of compounds of Formulas F and G using a metal such aszinc, the bromopyridine substrate (F, G) is dissolved in an aqueousbasic solvent medium and then treated with zinc metal. From about 1 toabout 4 molar equivalents of zinc metal (i.e., Zn dust, Zn powder, or ahigh surface area Zn solid), preferably 1-3 molar equivalents, may beused. The reduction is normally conducted in an aqueous solvent mediumof water containing a metal hydroxide such as potassium or sodiumhydroxide, where the concentration of the metal hydroxide in water mayrange from about 10 weight % to about 30 weight %. The reaction may beconducted at a temperature from about 10° C. to about 60° C., preferablyfrom about 20° C. to about 55° C., for a period of about 5 to about 36hours. It is preferred to use the metal reduction chemistry (i.e.,Zn/metal hydroxide) for the reduction of the 6-bromopicolinonitrile ofFormula F to produce the picolinonitrile of Formula I. After the metalreduction reaction is complete, the desired product is recovered byusing a mineral or organic acid workup and then employing standardisolation and purification techniques.

In one embodiment, the reductive removal of the bromo group andhydrolysis of the nitrile group of the compound of Formula F to producethe compound of Formula H can be conducted in a one-pot process usingzinc metal (i.e., Zn dust, Zn powder, or a high surface area Zn solid)and potassium hydroxide at elevated temperature. The temperature atwhich the one-pot process may be conducted is usually between about 75°C. and about 125° C. and preferably between about 80° C. and about 100°C. After the reaction is complete, the desired product may be isolatedby acidifying the reaction mixture and employing standard isolation andpurification techniques.

The products obtained by any of these processes, can be recovered byconventional means, such as evaporation, filtration or extraction, andcan be purified by standard procedures, such as by recrystallization orchromatography.

The following examples are presented to illustrate the disclosure.

EXAMPLES Example 1a Cyano(furan-2-yl)methanaminium bromide

To a magnetically stirred suspension of potassium cyanide (29.3 g, 450mmol) and ammonium acetate (116 g, 1500 mmol) in methanol (200 mL) wasadded furan-2-carbaldehyde (28.8 g, 300 mmol) at 0-5° C. The reactionmixture was stirred at 0-5° C. for 40-50 hours. After the reaction wascomplete as indicated by HPLC analysis, the reaction mixture was dilutedwith CH₂Cl₂ (300 mL) and 5% NaHCO₃ (300 mL). The aqueous layer wasextracted with additional CH₂Cl₂ (4×150 mL). The organic layers werecombined and concentrated under vacuum with EtOAc. The resultingresidual solution was dissolved in additional EtOAc (600 mL) and cooledto 5° C. A solution of 33% HBr (66.1 g, 270 mmol) in acetic acid wascharged slowly to the EtOAc solution to precipitate a solid. The solidwas filtered and washed with EtOAc. The collected solid was dried in airat room temperature to give cyano(furan-2-yl)methanaminium bromide (47g) in 77% yield: ¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (s, 3H), 7.94 (dd,J=1.9, 0.8 Hz, 1H), 6.80 (dt, J=3.4, 0.7 Hz, 1H), 6.63 (dd, J=3.4, 1.9Hz, 1H), 6.29 (d, J=1.8 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 145.60,142.13, 114.28, 112.43, 111.53, 37.54; HBr salt HRMS-ESI (m/z) calc'dfor [C₆H₆N₂O]⁺, 122.048 found, 123.055 [M+H]⁺; m.p. decomposed >120° C.

Example 1b Cyano(furan-2-yl)methanaminium bromide

To a magnetically stirred suspension of ammonium chloride (25.03 g, 468mmol) in MTBE (250 mL) was added furan-2-carbaldehyde (28.8 g, 300 mmol)and a solution of sodium cyanide (17.20 g, 351 mmol) in water (80 mL) atroom temperature. The reaction mixture was stirred at room temperaturefor 15 hours. After the reaction was complete, the aqueous layer wasremoved. The organic layer was washed with saturated NaHCO₃ solution(2×100 mL). The organic layer was dried over Na₂SO₄ and filtered. Theresulting filtrate was cooled to 5° C. and a solution of 33% HBr (57.4g, 234 mmol) in acetic acid was charged slowly into the solution toprecipitate a solid. The solid was filtered and washed with MTBE. Thecollected solid was dried in air at room temperature to givecyano(furan-2-yl)methanaminium bromide (29 g) in 54% yield. This sampleexhibited similar spectral properties to the sample prepared in Example1a.

Example 1c 4,6-Dibromo-3-hydroxypicolinonitrile

To a mechanically stirred solution of cyano(furan-2-yl)methanaminiumbromide (143 g, 704 mmol) in water (1408 mL) at 5° C. was slowly addedBr₂ (225 g, 1409 mmol) from a dropping funnel while maintaining thetemperature at <15° C. After a further 10-15 minutes (after bromineaddition was complete), sodium acetate (144 g, 1761 mmol) and methanol(281 mL) were added to the reaction mixture, followed by the dropwiseaddition of a second portion of Br₂ (109 mL, 338 g, 2113 mmol) whilemaintaining the temperature at <20° C. The reaction mixture was thenstirred overnight at room temperature. After the reaction was completeas indicated by HPLC analysis, the reaction mixture was cooled to 5-10°C., and slowly charged with an aqueous solution of 20% NaHSO₃ (704 mL)while keeping the temperature at <20° C. The resulting suspension wasstirred for 0.5 hr and then filtered. The filter cake was washed withwater, dried in air for several hours and then in a vacuum oven at 50°C. overnight to give 4,6-dibromo-3-hydroxypicolinonitrile (137 g) as alight yellow solid in 70% yield: ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s,1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 155.55, 135.72, 129.81, 125.96,121.61, 114.58; HRMS-ESI (m/z) calc'd for [C₆H₂Br₂N₂O]⁺, 275.8534.found, 275.851; mp 183-185° C.

Example 1d 4,6-Dibromo-3-hydroxypicolinonitrile (1-Pot Process)

To a magnetically stirred suspension of potassium cyanide (7.16 g, 110mmol) and ammonium acetate (10.02 g, 130 mmol) in methanol (50 mL) wasadded furan-2-carbaldehyde (9.61 g, 100 mmol) at room temperature. Thereaction mixture was stirred at room temperature overnight. After thereaction was complete as indicated by HPLC analysis, the reactionmixture was diluted with water (100 mL) and cooled to 5° C. Bromine (80g, 500 mmol) was charged slowly to the reaction while maintaining thetemperature at <20° C. The reaction mixture was warmed and stirredovernight at room temperature. After the reaction was complete asindicated by HPLC analysis, the reaction mixture was cooled to 5-10° C.,and an aqueous solution of 10% NaHSO₃ (100 mL) was slowly charged whilemaintaining the temperature at <20° C. The resulting suspension wasstirred for 0.5 hr and then filtered. The filter cake was washed withwater, dried in air for several hours and then in a vacuum oven at 50°C. overnight to give 4,6-dibromo-3-hydroxypicolinonitrile (8 g) as abrown solid in 28% yield. ¹H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H),8.19 (dd, J=4.4, 1.3 Hz, 1H), 7.56 (dd, J=8.6, 4.4 Hz, 1H), 7.47 (dd,J=8.6, 1.4 Hz, 1H); ¹³C NMR (101 MHz, DMSO) δ 157.69, 142.01, 128.86,124.41, 120.31, 115.99.

Example 1e 4,6-Dibromo-3-hydroxypicolinonitrile (Two Step Process)

To a mechanically stirred solution of cyano(furan-2-yl)methanaminiumbromide (10.15 g, 50 mmol) in water (100 mL) at 5° C. was slowly addedBr₂ (15.98 g, 100 mmol) from a dropping funnel while maintaining thetemperature at <15° C. After a further 30 minutes the reaction mixturewas slowly charged with an aqueous solution of 20% NaHSO₃ (50 mL) whilekeeping the temperature at <20° C. The resulting suspension was stirredfor 0.5 hr and then filtered. The filter cake was washed with water,dried in air for several hours and then in a vacuum oven at 50° C.overnight to give 3-hydroxypicolinonitrile (2.4 g) as a brown solid in40% yield: ¹H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.19 (dd, J=4.4,1.3 Hz, 1H), 7.56 (dd, J=8.6, 4.4 Hz, 1H), 7.47 (dd, J=8.6, 1.4 Hz, 1H);¹³C NMR (101 MHz, DMSO) δ 157.69, 142.01, 128.86, 124.41, 120.31,115.99; mp 203° C.

To a mechanically stirred solution of 3-hydroxypicolinonitrile (12.01 g,100 mmol) and sodium acetate (16.4 g, 200 mmol) in water (150 mL) andmethanol (50 mL) at 5° C. was slowly added Br₂ (47.9 g, 300 mmol) from adropping funnel while maintaining the temperature at <20° C. Thereaction mixture was then stirred overnight at room temperature. Afterthe reaction was complete as indicated by HPLC analysis, the reactionmixture was cooled to 5-10° C., and slowly charged with an aqueoussolution of 20% NaHSO₃ (100 mL) while keeping the temperature at <20° C.The resulting suspension was stirred for 0.5 hr and then filtered. Thefilter cake was washed with water, dried in air for several hours andthen in a vacuum oven at 50° C. overnight to give4,6-dibromo-3-hydroxypicolinonitrile (27 g) as a light yellow solid in97% yield. The sample exhibited similar spectral properties to othersamples of 4,6-dibromo-3-hydroxypicolinonitrile prepared herein.

Example 1f 4,6-Dibromo-3-hydroxypicolinonitrile (Biphasic Process)

To a magnetically stirred suspension of potassium cyanide (103 g, 1575mmol) and ammonium acetate (347 g, 4500 mmol) in ethyl acetate (1500 mL)and water (375 mL) was added furan-2-carbaldehyde (144 g, 1500 mmol) atroom temperature. The reaction mixture was stirred at room temperatureovernight. After the reaction was complete as indicated by ¹H NMRanalysis, the reaction mixture was diluted with 20% Na₂CO₃ (750 mL).After phase separation, the organic layer was washed with a saturatedsolution of aqueous NaCl (375 mL). The organic layer containing2-amino-2-(furan-2-yl)acetonitrile was extracted with 1953 mL of 3.7%aqueous hydrobromic acid (HBr) solution. The organic layer was extractedwith additional water (2×200 mL). The combined aqueous layers werecooled to 5° C. and bromine (959 g, 6000 mmol) was charged slowly viause of a peristaltic pump and Teflon tubing to the HBr solution whilemaintaining the temperature at <20° C. The reaction mixture was thenwarmed and stirred overnight at 25° C. After the reaction was complete,as indicated by ¹H NMR analysis, the reaction mixture was cooled to5-10° C., and then an aqueous solution of 40% NaHSO₃ (400 mL) was slowlycharged while maintaining the temperature at <20° C. The resultingsuspension was stirred for 0.5 hr and then filtered. The filter cake waswashed with water (2×200 mL), and dried at ambient temperature in theair to give 4,6-dibromo-3-hydroxypicolinonitrile (251 g) as a tan solidin 60% yield. ¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H); ¹³C NMR (101MHz, DMSO-d6) δ 155.57, 135.72, 129.77, 125.97, 121.60, 114.59. HRMS-ESI(m/z) calc'd for [C₆H₂Br₂N₂O]⁺, 275.8534. found, 275.8510. The tan solidwas found to contain about 94.5% of 4,6-dibromo-3-hydroxypicolinonitrileand less than about 6% of a mono-brominated intermediate product whichwas tentatively assigned as either 4-bromo-3-hydroxypicolinonitrile or6-bromo-3-hydroxypicolinonitrile as determined by MS analysis.

Example 1g 4,6-Dibromo-3-hydroxypicolinonitrile (Biphasic Process)

A 30 L jacketed glass reactor was charged with ammonium acetate (3371 g,43.73 mol), ethyl acetate (13,144 g), potassium cyanide (1,000 g, 15.38mol), and then water (1819 g). The agitation was turned on to 150 rpm,and then furfural (1,398 g, 14.56 mol) was fed into the reactor via apump at room temperature. The reaction was allowed to stir overnight atroom temperature, at which point the reaction was >97% complete asdetermined by ¹H NMR analysis. A solution of 16% sodium carbonate inwater (7300 g) was added to the reaction mixture. The reaction mixturewas allowed to stir for 1 h. After settling, the aqueous phase wasremoved, and then the organic phase was washed with saturated brine(5677 g, 23%). After removing the brine, the organic solution wastransferred via pump to a 50 L jacketed glass reactor which contained DIwater (8896 g). 48% aqueous HBr (2466 g, 14.6 mol) was diluted with DIwater (5668 grams) and the resulting HBr solution was then pumped intothe 50 L reactor with the agitation at 150 rpm at room temperature.After allowing the mixture to stir for 1 hour, the phases were allowedto separate for 45 minutes. The aqueous phase was drained into two 5gallon carboys. The organic phase was then washed 2 times with about2,000 gram of DI water. The DI water washes were placed in the carboys.The organic phase was discarded and then the 50 L reactor was washedwith 500 mL of ethyl acetate and 500 mL of DI water. The aqueous phase(24,536 grams) in the two carboys was transferred back to the 50 Lreactor, and then the residual HBr salt in the carboys was washed intoreactor with a total of 1945 grams of DI water. The aqueous phase in thereactor was then cooled to about 0° C. and allowed to mix overnight.Bromine (9311 grams, 56.1 mol) was then added to the reaction over 45minutes (initial temperature of about 0° C.), which resulted in atemperature rise to 25° C. During the bromine addition, a materialprecipitated from solution and then re-dissolved. About 1 h after thefeed of bromine was completed, solids began to reform in the solution.The reaction was then heated at 35° C. for about 24 h. The reaction wasthen cooled to <10° C., and then 40% aqueous sodium bisulfite (3757 g)was added to quench the excess bromine. The solids were collected byfiltration and washed with DI water (5 L) until the wash liquid wascolorless. The resulting wet cake was allowed to dry in glass traysuntil no further weight loss was observed, which resulted in 2590 gramsof a free flowing tan powder. ¹H NMR assay indicated that the solid was97.8 wt % 4,6-dibromo-3-hydroxy-picolinonitrile. The yield based on theassay was 62.6%. ¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.75 (d, J=8Hz, 0.03H), 7.43 (d, J=8 Hz, 0.03H); ¹³C NMR (101 MHz, DMSO) δ 155.47,135.68, 129.86, 125.88, 125.88, 121.63, 114.50. HRMS (m/z) Positive Ionmode [M+1] calcd for [C₆H₃Br₂N₂O]⁺ 276.8607. found 276.8609.

Example 1i 3-Hydroxypicolinonitrile (Biphasic Process)

To an inserted 6 L straight-walled jacketed reactor was added 346 gramsof ammonium acetate (4500 mmol), 1500 mL of ethyl acetate (EtOAc), 300mL of DI water, and 102.5 grams of potassium cyanide (KCN, 1574 mmol).The KCN jar and addition funnel were then rinsed with about 75 mL ofwater to wash any residual KCN into the reactor. The reaction vessel wasclosed, cooled to 15° C. and the agitation was then set to 260 rpm.Furfural (144 g, 1500 mmol) was then added to the reactor via syringeover 5 minutes. The temperature in the reactor increased from about 15°C. to 22° C. The reaction was allowed to stir overnight (22° C.). Theagitation was turned off to allow the phases to be separated. Theorganic phase was then sampled for ¹H NMR analysis. The reaction wasshown to be >99% converted to the desired product. With agitation (250rpm), 750 mL of 20% aqueous sodium carbonate was added to the reactorand allowed to stir for 10 minutes. The aqueous phase containing thesodium carbonate solution was removed and then the remaining organicphase was washed with 400 mL of saturated brine. 170 mL of aqueous 48%HBr (1 equiv., 1345 mmol) diluted in about 1300 ml of DI water was addedto the reactor containing the organic phase. The reactor containing theaqueous HBr-organic phase was mixed (250 rpm) for 15 minutes. Aftersettling, the aqueous layer was drained into a 5 L receiving vessel. Theorganic layer was then washed with an additional 250 mL of DI waterwhich was also drained into the 5 L vessel. The reactor was then emptiedand rinsed with 300 mL of EtOAc. The aqueous layer in the 5 L vessel wasthen vacuum transferred back up to the 5 L straight-walled reactor. The5 L receiving vessel was washed with 200 mL of water which was alsoadded to the reactor. The contents of the reactor were then agitated,cooled to 0° C. and then bromine (240 g, 1500 mmol) was added via aTeflon line through a peristaltic pump over 30 minutes, which led to atemperature rise to 19° C. and the formation of a precipitate. Thereaction was allowed to stir overnight at room temperature. 40% aqueoussodium bisulfite (250 mL) was then added slowly to the reaction tomaintain a temp <40° C. After the bromine was quenched, the solids werecollected on a frit and washed with water and dried to yield3-hydroxypicolinonitrile in 47% yield (85 g) as a red crystalline solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.67 (s, 1H), 8.21 (dd, J=4.4, 1.4 Hz, 1H),7.57 (dd, J=8.6, 4.4 Hz, 1H), 7.50 (dd, J=8.6, 1.4 Hz, 1H)¹³C NMR (101MHz, DMSO) δ 157.66, 141.92, 128.72, 124.35, 120.34, 115.97. HRMS (m/z)Positive Ion mode [M+1] calcd for [C₆H₅N₂O]⁺121.0397. found 121.0400.

Example 2a 6-Bromo-4-methoxy-3-hydroxypicolinonitrile

To a magnetically stirred solution of4,6-dibromo-3-hydroxypicolinonitrile (152 g, 547 mmol) in DMSO (820 mL)was added a 30% NaOMe in MeOH (492 g, 2.73 mol) solution at roomtemperature. The reaction mixture was warmed to 50-55° C. and stirredovernight. The reaction mixture was then cooled to 15-20° C., quenchedby slow addition of 1.5N HCl (1500 mL) to adjust the pH to about 2-3,and then extracted with CH₂Cl₂ (2×1000 mL). The combined organic layerswere washed with 0.1N HCl (1000 mL) and concentrated to ca. 500 mlvolume, charged with 100 mL of acetonitrile (ACN), and finallyconcentrated to dryness. The crude product obtained was washed with 0.1NHCl (1000 mL) and filtered. The filter cake was washed with water, driedin air for several hours and then in a vacuum oven at 50° C. overnightto give 6-bromo-3-hydroxy-4-methoxypicolinonitrile (83 g) in 66% yieldas a brown solid: ¹H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 7.48 (s,1H), 3.97 (s, 3H); ¹³C NMR (101 MHz, DMSO-d6) δ 156.54, 149.35, 131.02,118.54, 114.91, 114.57, 57.20; HRMS-ESI (m/z) calc'd for [C₇H₅BrN₂O₂]⁺,227.9533. found, 227.9534; m.p. 168° C. The aqueous filtrate wasextracted with CH₂Cl₂ (twice). The organic layers were combined andconcentrated with ACN as described herein. The crude solid was dissolvedin ACN (50 mL) and added slowly into 0.1N HCl (400 mL) at roomtemperature. The precipitated solid was stirred for 1 h and filtered.The filter cake was washed with water and dried to give additional6-bromo-3-hydroxy-4-methoxypicolinonitrile (13 g) in 10% yield.

Example 2b 6-Bromo-4-methoxy-3-hydroxypicolinonitrile

4,6-dibromo-hydroxypicolinonitrile (500 grams, 1806 mmol) was dissolvedin a mixture of 500 mL of anhydrous DMSO and 20 mL of anhydrous MeOH atroom temperature under an inert atmosphere. Sodium methoxide (250 grams,4606 mmol) and 500 mL of anhydrous DMSO were then charged to a 5-L,4-neck reaction flask which had been purged with nitrogen. The reactionflask was outfitted with a condenser (w/N₂ line), thermal well,mechanical stirrer and a septum (with a ⅛″ feed line). The solution ofthe 4,6-dibromo-hydroxypicolinonitrile in DMSO-MeOH was then fed to thereaction flask at a rate of 15-20 g per minute via a peristaltic pumpthrough the ⅛″ Teflon tubing. When the reaction temperature reached 55°C., a cold water bath was placed around the flask. The reaction wasmaintained between 50 and 55° C. during the feed. The reaction was thenmaintained at around 54° C. for 1.5 h after addition was complete. Afterdetermining the reaction was complete by ¹H NMR analysis, the reactionmixture was cooled to <30° C. with an ice bath. At 30° C., 2 L of waterwere added to the reaction mixture which caused the solution to warmto >40° C. The reaction mixture was cooled to 30° C., and then 10 Nsulfuric acid was added via an addition funnel until the pH was around2.5, which resulted in the precipitation of a white solid. At pH 2.5,the reaction was allowed to stir for 30-60 minutes during which time thereaction mixture was cooled to 15° C. The solid was filtered and thenwashed with water until the filtrate was colorless. The solid was driedin a vacuum oven at 50° C. until the weight remained constant. The solidwas a slightly tan colored powder (344 g, 83% yield): ¹H NMR (400 MHz,DMSO-d6) δ 11.64 (s, 1H), 7.48 (s, 1H), 3.97 (s, 3H); ¹³C NMR (101 MHz,DMSO-d6) δ 156.54, 149.35, 131.02, 118.54, 114.91, 114.57, 57.20.

Example 2c 6-Bromo-4-methoxy-3-hydroxypicolinonitrile

25.1 kg of dimethyl sulfoxide (DMSO) was loaded into a glass lined steel(GLS) reactor and heated under jacket temperature control set point of100° C. with a purge of nitrogen at 4 liter/min at atmospheric pressurefor 18 hours. The jacket temperature was reduced to 35° C. and the DMSOwas allowed to cool. 4,6-dibromo-3-hydroxypicolinonitrile (8.0 kg, 28.8mol) was loaded in to the reactor with the vent open and a 1 liter/minnitrogen purge. The reactor was set to control pressure at 25 mm Hg(actual pressure controlled at a nominal pressure of 35-60 mm Hg),agitated at 90 rpm and put under master temperature control, whichutilized the actual reaction mixture, of 30° C. The overhead heatexchanger, used to condense methanol, was operated at −5 to −10° C. A25% by weight sodium methoxide mixture in methanol (16.51 Kg, 76.4 mol)was pumped into the reactor over about 30-45 minutes. Methanol wascontinuously stripped from the reaction mixture and condensed. After themethoxide had been added, the reaction temperature was increased to 53°C. over 1.5 hours. Approximately 5.5 hours after reaching 52-53° C., thereaction was sampled and determined to be complete by ¹H NMR. Thereaction mixture was cooled under a jacket control temperature of 35° C.and methanol was flushed through process sample lines and the sodiummethoxide feed addition pump. 25 kg of de-ionized (DI) water was addedto the reaction mixture and the entire contents transferred to astainless steel (SS) reactor. An additional 25 kg of DI water was loadedinto the GLS reactor and the contents transferred to the SS reactor.26.6 kg of a 20% aqueous sulfuric acid mixture was added to the basic(pH 13) aqueous reaction product, sodium6-bromo-2-cyano-4-methoxypyridin-3-olate, to result in a pH<2. Theneutralized 6-bromo-4-methoxy-3-hydroxy picolinonitrile was isolatedusing a centrifuge. The wetcake was washed using 5 gallons of DI waterthat was loaded into the SS reactor to flush residual solids to thecentrifuge. The solids were spun dry under nitrogen in the centrifugeand the wetcake was further dried under a purge of dry nitrogen until nofurther weight loss was observed. 5.011 kg of dried6-bromo-4-methoxy-3-hydroxypicolinonitrile was obtained as an off-whitesolid (76% yield). ¹H NMR assay of the material indicated that theproduct was >99.5% pure.

Example 2d 6-Bromo-4-methoxy-3-hydroxypicolinonitrile

To a slurry of sodium methoxide (15.2 g, 282 mmol) in 35 mL of anhydrousdimethyl sulfoxide (DMSO) was added a solution of4,6-dibromo-3-hydroxypicolinonitrile (30 g, 108 mmol) in anhydrous DMSO(30 mL). The solution was added over 30 minutes and the reaction mixturewas maintained below 55° C. during the addition. The reaction solutionwas heated for an additional 1.5 hours after the feed was complete. Theresulting reaction mixture was cooled to <30° C., and then 120 mL of DIwater was added. The reaction mixture was allowed to cool to about 25°C. The pH of the reaction mixture was adjusted to about 2 with 40%sulfuric acid, which resulted in the precipitation of a solid. The solidwere collected by filtration, washed with 75 mL of pH 1.5 sulfuric acidfollowed by 25 mL of DI water. The solid was then allowed to dry toyield 20.7 g (83.7% yield) of desired product. ¹H NMR (400 MHz, DMSO-d₆)δ 11.60 (s, 1H), 7.47 (s, 1H), 3.98 (s, 3H). ¹³C NMR (101 MHz, DMSO) δ156.52, 149.35, 130.99, 118.55, 114.89, 114.52, 57.18.

Example 2e 6-Bromo-4-methoxy-3-hydroxypicolinonitrile

To a solution of 4,6-dibromo-3-hydroxypicolinonitrile (1.11 g, 4.0 mmol)in methanol (7.5 mL) in a 40 mL microwave tube was added a solution of25 wt % NaOMe in MeOH (2.59 g, 12 mmol). The solution was heated at 110°C. under microwave irradiation for 12 h. The reaction mixture was thencooled to 15-20° C., quenched by slow addition of 2 M HCl to adjust thepH to about 4-5. The reaction mixture was concentrated by rotaryevaporation. The mixture was purified by flash chromatography on silicagel, eluting with methanol/CH₂Cl₂ to give 0.53 g (58% yield) of solid(mp=177-180° C.). ¹H NMR (400 MHz, Methanol-d₄) δ 7.33 (d, J=1.0 Hz,1H), 4.01 (s, 3H). ¹³C NMR (101 MHz, Methanol-d₄) δ 157.96, 150.91,132.58, 119.91, 115.50, 115.09, 57.66.

Example 2f 6-Bromo-4-ethoxy-3-hydroxypicolinonitrile

To a magnetically stirred solution of4,6-dibromo-3-hydroxypicolinonitrile (5.40 g, 19.4 mmol) in DMSO (30 mL)was added a 21% NaOEt in EtOH (31.5 g, 97 mol) solution at roomtemperature. The reaction mixture was heated at 55° C. for 18 h. Thereaction mixture was then cooled to 15-20° C. and poured into a mixtureof 25 mL of concentrated HCl and 80 g of ice. A tan precipitate formed.The mixture was extracted into EtOAc (4×75 mL). The combined organicswere washed with water (5×100 mL) and then brine. The extracts weredried (MgSO₄) and rotary evaporated to a tan solid. The solid wastriturated with 1:1 hexane-ether (3×20 mL) and then dried in air toyield a light tan solid (4.39 g, 93% yield, m.p.=175-177° C.). ¹H NMR(400 MHz, DMSO-d₆) δ 11.42 (s, 1H), 7.45 (s, 1H), 4.25 (q, J=7.0 Hz,2H), 1.38 (t, J=7.0 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ 155.81, 149.32,131.15, 118.63, 114.94, 114.87, 65.74, 13.94. HRMS-ESI (m/z) calc'd for[C₈H₇BrN₂O₂]⁺, 241.9691. found, 241.9690.

Example 2g 6-Bromo-3-hydroxy-4-methoxypicolinic acid

To a magnetically stirred solid sample of6-bromo-3-hydroxy-4-methoxypicolinonitrile (88 g, 384 mmol) was added66% H₂SO₄ (384 mL) at room temperature. The resulting mixture was warmedand stirred overnight at 90-95° C. After HPLC indicated the reaction wascomplete, the reaction mixture was cooled to 30-40° C. and transferredslowly to a flask charged with water (3072 g) to precipitate theproduct. The resulting suspension was stirred for 0.5 hr. The resultingprecipitate was filtered, washed with water, and dried in air overnightto give 6-bromo-3-hydroxy-4-methoxypicolinic acid (95 g) as an off-whitesolid in 100% yield: ¹H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 3.97 (s,3H); ¹³C NMR (101 MHz, DMSO-d6) δ 170.12, 156.58, 149.09, 130.19,129.86, 114.46, 56.79; HRMS-ESI (m/z) [M+H]+ calcd for C₇H₆BrNO₄,246.948. found, 246.948; m.p. 167-170° C.

Example 2h 6-Bromo-4-ethoxy-3-hydroxypicolinic acid

6-Bromo-4-ethoxy-3-hydroxypicolinonitrile (906 mg, 3.73 mmol) was addedto 66% H₂SO₄ (15 mL) at room temperature. The resulting mixture wasmagnetically stirred and heated at 90° C. for 17 h, cooled to ambienttemperature, and poured into 12 g ice. A solution of 50% NaOH was addeduntil a tan solid precipitated. The solid was extracted into EtOAc (3×25mL), dried over MgSO₄, and rotary evaporated to 923 mg of whitecrystalline solid (94% yield, m.p.=152-155° C.). ¹H NMR (400 MHz,DMSO-d₆) δ 11.5 (br, 1H), 7.36 (s, 1H), 4.19 (q, J=7.0 Hz, 2H), 1.36 (t,J=7.0 Hz, 3H). HRMS-ESI (m/z) [M+H]+ calcd for C₈H₈BrNO₄, 260.9637.found, 260.964.

Example 2i 3-Hydroxy-4-methoxypicolinic acid

Batch 1:

To 3-hydroxy-6-bromo-4-methoxypicolinic acid (47.5 g) and EtOH (576 mL)in a Parr shaker bottle (2 L) was added triethylamine (40.7 g, 402mmol). Then under a nitrogen atmosphere 5% Pd/C (20 g, 9.6 mmol; 5 mol%) was added to the bottle. The reaction slurry was placed on a Parrshaker and the bottle placed under hydrogen gas (40-45 psi) and shaked.After completion of the reaction as indicated by HPLC analysis, thehydrogen gas was removed under vacuum and replaced with nitrogen gas.The reaction slurry was filtered through a pad of celite and the celitepad was washed with fresh ethanol.

Batch 2:

To 3-hydroxy-6-bromo-4-methoxypicolinic acid (47.5 g) and EtOH (576 mL)in a Parr shaker bottle (2 L) was added triethylamine (40.7 g, 402mmol). Then under a nitrogen atmosphere added 5% Pd/C (10 g, 4.8 mmol;2.5 mol %). The 2^(nd) reaction was completed as described for the1^(st) batch. The ethanolic filtrates for the 2 batches were combinedand concentrated to give a solid. The solid was diluted with 0.2N HCl(400 mL) to adjust the pH to about 1-2 and the resulting suspension wasstirred for 10-15 minutes at room temperature. The solid was thencollected by filtration, washed with water and dried in air for severalhours and then in a vacuum oven at 50° C. to give3-hydroxy-4-methoxypicolinic acid (55 g) as an off-white solid in 85%yield: ¹H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=6.4 Hz, 1H), 7.40 (d,J=6.5 Hz, 1H), 4.04 (s, 3H); ¹³C NMR (101 MHz, DMSO-d6) δ 164.16,162.03, 152.52, 132.32, 126.57, 109.13, 57.35; HRMS-ESI (m/z) calcd forC₇H₇NO₄, 169.0379. found, 169.0375; m.p. 219° C.

Example 2j 3-Hydroxy-4-ethoxypicolinic acid

To 6-bromo-4-ethoxy-3-hydroxypicolinic acid (739 mg) and EtOH (20 mL) ina Parr shaker bottle (0.5 L) was added triethylamine (599 mg, 5.92mmol). 5% Pd/C (300 mg, 0.141 mmol; 5 mol %) was added to the bottle.The reaction mixture was shaken under hydrogen gas (45 psi) for 22 h.The reaction mixture was filtered through a pad of celite, and thecelite pad was washed with ethanol. The filtrate was rotary evaporatedto a white solid (1.047 g) which was then slurried in 15 mL of 0.1M HCland filtered. Solid was washed with 5 mL of 0.1M HCl and then 5 mLwater. Solid was dried in air to give 402 mg (78% yield, m.p.=216-219°C.) of off-white powder. ¹H NMR showed the presence of 7% Et₃NHCl inaddition to product resonances. ¹H NMR (400 MHz, DMSO-d₆) δ 14.4 (br,1H), 8.01 (d, J=6.4 Hz, 1H), 7.38 (d, J=6.4 Hz, 1H), 4.32 (q, J=7.0 Hz,2H), 1.41 (t, J=7.0 Hz, 3H). ¹³C {¹H} NMR (DMSO-d₆. 126 MHz) δ 164.33,161.13, 152.37, 132.44, 126.92, 109.53, 66.02, 14.05. HRMS-ESI (m/z)[M+H]+ calcd for C₈H₉BrO₄, 183.0532. found, 183.0536.

Example 2k 3-Hydroxy-4-methoxypicolinonitrile

A suspension of 6-bromo-3-hydroxy-4-methoxypicolinonitrile (7.5 g, 32.7mmol), Zn dust (4.28 g, 65.5 mmol) and 20% aqueous KOH (100 mL) wasstirred overnight at room temperature. After completion of the reactionas indicated by HPLC analysis, the reaction mixture was filtered throughcelite. The aqueous filtrate was cooled to 5° C. and adjusted to a pH ofabout 3-4 with 3N HCl (˜125 mL). The precipitated solid was filtered,washed with water and dried in air and then in a vacuum oven at 50° C.to give 3-hydroxy-4-methoxypicolinonitrile (4 g) as a brown solid in 81%yield: ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.08 (d, J=5.3 Hz,1H), 7.28 (d, J=5.3 Hz, 1H), 3.94 (s, 3H); ¹³C NMR (101 MHz, DMSO-d6) δ154.69, 148.59, 143.51, 119.84, 116.07, 110.54, 56.36; HRMS-ESI (m/z)calcd for C₇H₆N₂O₂, 150.043. found, 150.0429; m.p. 224° C.

Example 21 3-Hydroxy-4-methoxypicolinic acid

A 1 L, 3-neck round bottom flask was charged with 125 grams of KOH (1952mmol, 88% assay for KOH) and then 400 grams of water. The flask wasoutfitted with a mechanical stirrer, thermal well, and a condenser (w/N2 inlet). The solution was mixed until the KOH dissolved.3-Hydroxy-4-methoxypicolinonitrile (50 g, 334 mmol) was then added tothe solution, which did not result in an exotherm. The reaction washeated to 90° C. After the reaction was considered complete by NMRanalysis (12 h), the reaction solution was allowed to cool to ambienttemperature and allowed to stand overnight. 12N HCl was added until thepH was 2-3, which caused the product to precipitate out of solution. Thesolids were collected by filtration and washed with 10 mL of MeOH andthen 10 mL of MTBE. The product was allowed to dry overnight and thenwas placed in the vacuum oven for 4 hours at 60° C. 49.2 grams of3-hydroxy-4-methoxy picolinic acid was obtained as an off-white solid(87.2% yield); ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (d, J=6.4 Hz, 1H), 7.39(d, J=6.5 Hz, 1H), 4.04 (s, 3H); ¹³C NMR (101 MHz, DMSO-d6) δ 164.16,162.03, 152.52, 132.32, 126.57, 109.13, 57.35; HRMS-ESI (m/z) calcd forC₇H₇NO₄, 169.0379. found, 169.0375.

Example 2m 3-Hydroxy-4-methoxypicolinic acid

A 1 L, 3-neck round bottom flask with a mechanical stirrer was chargedwith 6-bromo-3-hydroxy-4-methoxypicolinonitrile (45.8 g, 200 mmol) andzinc dust (14.38 g, 220 mmol) in water (200 mL). 45% KOH (125 g, 1000mmol) was charged slowly at rt. The reaction was heated to 90° C. Afterthe reaction was considered complete by HPLC analysis (20 h), thereaction solution was allowed to cool to ambient temperature. Thereaction mixture was filtered through celite. The filtrate was cooledwith an ice bath and then 12N HCl (ca. 90 mL) was added until the pH was0.9. The solids were collected by filtration and washed with 0.1N HCland water. The product was allowed to dry overnight and then was placedin the vacuum oven overnight at 50° C. 3-hydroxy-4-methoxy picolinicacid was obtained as an off-white solid (26.9 g, 80% yield): ¹H NMR (400MHz, DMSO-d6) δ 8.04 (d, J=6.4 Hz, 1H), 7.39 (d, J=6.5 Hz, 1H), 4.04 (s,3H); ¹³C NMR (101 MHz, DMSO-d6) δ 164.16, 162.03, 152.52, 132.32,126.57, 109.13, 57.35; HRMS-ESI (m/z) calcd for C₇H₇NO₄, 169.0379.found, 169.0375.

Example 2n 3-Hydroxy-4-methoxypicolinic acid

To a magnetically stirred solid of 3-hydroxy-6-bromo-4-methoxypicolinicacid (3.9 g, 26 mmol) was added 40% aqueous H₂SO₄ (125 mL) at roomtemperature. The mixture was then warmed and stirred overnight at 90° C.After HPLC analysis indicated the reaction was complete, the reactionmixture was cooled to 5° C., and 25% aqueous NaOH (˜250 mL) was chargedslowly to the reaction mixture to adjust the pH to about 1-2. Theresulting suspension was stirred for 10-15 minutes at room temperatureand the solid product was collected by filtration. The filter cake waswashed with water and dried in air for several hours and then in avacuum oven at 50° C. to give 3-hydroxy-4-methoxypicolinic acid (3.1 g)as a brown solid in 70% yield: m.p. 227° C. ¹H NMR (400 MHz, DMSO-d6) δ8.04 (d, J=6.4 Hz, 1H), 7.40 (d, J=6.5 Hz, 1H), 4.04 (s, 3H); ¹³C NMR(101 MHz, DMSO-d6) δ 164.16, 162.03, 152.52, 132.32, 126.57, 109.13,57.35.

What is claimed is:
 1. A biphasic process for the preparation of thecompound of Formula A

comprising the steps of: a) creating a first mixture by combiningtogether a 2-phase water-organic solvent system, an ammonia source, acyanide source and a furan-2-aldehyde of Formula B

b) separating a second mixture from the first mixture which includes thecompound of Formula C as a solution in the organic solvent;

c) adding an aqueous solution of a mineral acid to the second mixture toform a third mixture; d) separating a fourth mixture from the thirdmixture which is an aqueous mixture that includes the compound offormula D;

wherein X is Br, HSO₄, NO₃ or H₂PO₄; e) adding a brominating agent tothe fourth mixture to form a fifth mixture; and f) isolating thecompound of Formula A from the fifth mixture.
 2. The process of claim 1wherein the organic solvent is at least one organic solvent selectedfrom the group of organic solvents consisting of: diethyl ether, methylt-butyl ether, methylene chloride, ethyl acetate,2-methyltetrahydrofuran, toluene and xylene.
 3. The process of claim 1further comprising the steps of: a) creating a sixth mixture whichincludes the alkali metal alkoxide of Formula EMOR¹  E wherein M is Na or K, and R¹ is a C₁-C₃ alkyl; and the compoundof Formula A; b) heating the mixture; and c) isolating a compound ofFormula F from the sixth mixture;

wherein R¹ is a C₁-C₃ alkyl.
 4. The process of claim 3 furthercomprising the steps of: a) creating a seventh mixture which includesthe compound of Formula F, water, and at least one of a mineral acid anda strong base; b) heating the mixture; and c) isolating the compound ofFormula G

wherein R¹ is a C₁-C₃ alkyl; from the seventh mixture.
 5. The process ofclaim 4 wherein the seventh mixture includes the compound of Formula F,water, and a mineral acid.
 6. The process of claim 4 wherein the seventhmixture includes the compound of Formula F, water, and a strong base. 7.The process of claim 4 further comprising the following steps: a)creating an eighth mixture which includes the compound of Formula G anda reducing agent; and b) isolating the compound of Formula H from theeighth mixture;

wherein R¹ is a C₁-C₃ alkyl.
 8. The process of claim 3 furthercomprising the following steps: a) creating a ninth mixture whichincludes the compound of Formula F and a reducing agent; and b)isolating the compound of Formula I from the ninth mixture;

wherein R¹ is a C₁-C₃ alkyl.
 9. The process of claim 8 furthercomprising the steps of: a) creating a tenth mixture which includes thecompound of Formula I, water, and one of a mineral acid and a strongbase; and b) isolating a compound of Formula H from the tenth mixture;

wherein R¹ is a C₁-C₃ alkyl.
 10. The process of claim 9 furthercomprising the step of; heating the tenth mixture.
 11. The process ofclaim 9 wherein the tenth mixture includes the compound of Formula I,water, and a mineral acid.
 12. The process of claim 9 wherein the tenthmixture includes the compound of Formula I, water, and a strong base.13. A process for preparing the compound of Formula F

wherein R¹ is a C₁-C₃ alkyl; comprising the steps of: a) creating amixture which includes at least one alkali metal alkoxide of Formula EMOR¹  E wherein M is Na or K, and R¹ is a C₁-C₃ alkyl; and the compoundof Formula A;

b) heating the mixture; and c) isolating a compound of Formula F fromthe mixture.
 14. The process of claim 13 wherein M is Na and R¹ is aC₁-C₃ alkyl.
 15. The process of claim 13 further comprising a solventmixture comprised of a protic solvent and a polar aprotic solvent. 16.The process of claim 15 wherein the protic solvent is selected is atleast one solvent selected from the group consisting of: methanol andethanol.
 17. The process of claim 15 wherein the aprotic solvent is atleast one solvent selected from the group consisting of: DMSO, DMF,sulfolane and NMP.
 18. The process of claim 15 wherein the volumepercent ratio of the protic solvent to the polar aprotic solvent in thesolvent mixture is from about 100:0 to about 0:100.